S100A6 Amyloid Fibril Formation Is Calcium-modulated and Enhances Superoxide Dismutase-1 (SOD1) Aggregation

Botelho, Hugo M.; Leal, Sónia S.; Cardoso, Isabel; Yanamandra, Kiran; Morozova‐Roche, Ludmilla A.; Fritz, Günter; Gomes, Cláudio M.

doi:10.1074/jbc.m112.396416

Cited by 39 publications

(34 citation statements)

References 70 publications

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“…This has precisely been demonstrated for S100A6, which was shown to undergo amyloid β-aggregation both at neutral and acidic pH, albeit with very distinct timescales [23]. Indeed, S100A6 has been included in the present study as a control and was further analyzed in respect to structural changes occurring upon acidification.…”

Section: Resultssupporting

confidence: 60%

“…Recently, we showed that S100A6 forms amyloid fibrils under physiological conditions and that the native protein nucleates Cu/Zn superoxide dismutase (SOD1) fibrillation, shortening its nucleation process. These findings suggest a novel role for S100A6 aggregation in human neuropathologies, particularly in amyotrophic lateral sclerosis (ALS) [23]. Taking into account this background, we herein report a study in which we have analyzed seven human S100 proteins for relationships between aggregation propensity, disordered regions and amyloid formation, combining computational and biophysical tools.…”

Section: Introductionmentioning

confidence: 99%

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Intrinsically Disordered and Aggregation Prone Regions Underlie β-Aggregation in S100 Proteins

et al. 2013

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S100 proteins are small dimeric calcium-binding proteins which control cell cycle, growth and differentiation via interactions with different target proteins. Intrinsic disorder is a hallmark among many signaling proteins and S100 proteins have been proposed to contain disorder-prone regions. Interestingly, some S100 proteins also form amyloids: S100A8/A9 forms fibrils in prostatic inclusions and S100A6 fibrillates in vitro and seeds SOD1 aggregation. Here we report a study designed to investigate whether β-aggregation is a feature extensive to more members of S100 family. In silico analysis of seven human S100 proteins revealed a direct correlation between aggregation and intrinsic disorder propensity scores, suggesting a relationship between these two independent properties. Averaged position-specific analysis and structural mapping showed that disorder-prone segments are contiguous to aggregation-prone regions and that whereas disorder is prominent on the hinge and target protein-interaction regions, segments with high aggregation propensity are found in ordered regions within the dimer interface. Acidic conditions likely destabilize the seven S100 studied by decreasing the shielding of aggregation-prone regions afforded by the quaternary structure. In agreement with the in silico analysis, hydrophobic moieties become accessible as indicated by strong ANS fluorescence. ATR-FTIR spectra support a structural inter-conversion from α-helices to intermolecular β-sheets, and prompt ThT-binding takes place with no noticeable lag phase. Dot blot analysis using amyloid conformational antibodies denotes a high diversity of conformers; subsequent analysis by TEM shows fibrils as dominant species. Altogether, our data suggests that β-aggregation and disorder-propensity are related properties in S100 proteins, and that the onset of aggregation is likely triggered by loss of protective tertiary and quaternary interactions.

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Section: Resultssupporting

confidence: 60%

Section: Introductionmentioning

confidence: 99%

Intrinsically Disordered and Aggregation Prone Regions Underlie β-Aggregation in S100 Proteins

et al. 2013

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“…Interestingly, S100A6 protein's capacity to form fibrils was also affected by calcium (Botelho et al . ). So far, there is no proof of an in vivo interaction between these two proteins or its association with a diseased‐state.…”

Section: Discussionmentioning

confidence: 97%

EFhd2 is a novel amyloid protein associated with pathological tau in Alzheimer's disease

Ferrer-Acosta

Rodríguez-Cruz

Orange

et al. 2013

Journal of Neurochemistry

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EFhd2 is a conserved calcium binding protein, abundant within the central nervous system. Previous studies identified EFhd2 associated with pathological forms of tau proteins in the tauopathy mouse model JNPL3, which expresses the human tauP301L mutant. This association was validated in human tauopathies, such as Alzheimer’s disease (AD). However, the role that EFhd2 may play in tauopathies is still unknown. Here, we show that EFhd2 formed amyloid structures in vitro, a capability that is reduced by calcium ions. Electron microscopy (EM) analyses demonstrated that recombinant EFhd2 formed filamentous structures. EM analyses of sarkosyl insoluble fractions derived from human AD brains also indicated that EFhd2 co-localizes with aggregated tau proteins and formed granular structures. Immunohistological analyses of brain slices demonstrated that EFhd2 co-localizes with pathological tau proteins in AD brains, confirming the co-aggregation of EFhd2 and pathological tau. Furthermore, EFhd2’s coiled-coil domain mediated its self-oligomerization in vitro and its association with tau proteins in JNPL3 mouse brain extracts. The results demonstrate that EFhd2 is a novel amyloid protein associated with pathological tau proteins in AD brain and that calcium binding may regulate the formation of EFhd2’s amyloid structures. Hence, EFhd2 may play an important role in the pathobiology of tau-mediated neurodegeneration.

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“…The protein appears to be regulated by calcium which binds to two EF-hand calcium binding sites within the protein. The binding of calcium is thought to induce conformational change in the protein which is involved in the regulation of a number of processes including cell proliferation and differentiation, calcium homeostasis, cell degeneration, and cytoskeletal dynamics via signal transduction pathways (21,22).…”

Section: Resultsmentioning

confidence: 99%

S100A6 expression in cutaneous smooth muscle neoplasms

Idriss

Elston

2015

APMIS

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The S100A6 protein is expressed in a variety of tissues and distinct staining patterns in S100A6 immunohistochemistry may be useful in the differential diagnosis of difficult lesions. We evaluated the staining pattern of the S100A6 antibody in 22 cases each of pilar leiomyoma (LM), angioleiomyoma (ALM), and cutaneous leiomyosarcoma (LMS). S100A6 labeled both the nucleus and cytoplasm of myocytes in positive cases. About 64% of LM and 86% ALM had positive staining to the S100A6 antibody but predominantly in a weak staining pattern. In contrast, 95% of the LMS exhibited moderate to strong staining with the S100A6 antibody. The difference in the frequency of positive cases was statistically significant in the LM vs LMS comparison (p = 0.025), but we found intensity of staining to be of greatest practical utility. Analysis between the groups taking in to consideration differences in intensity of staining using the nonparametric rank sum (Mann-Whitney U test) demonstrated that there was a statistically significant difference between LM and LMS and between ALM and LMS. Weak or absent S100A6 staining supports a diagnosis of LM, whereas strong positive staining supports a diagnosis of LMS.

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S100A6 Amyloid Fibril Formation Is Calcium-modulated and Enhances Superoxide Dismutase-1 (SOD1) Aggregation

Cited by 39 publications

References 70 publications

Intrinsically Disordered and Aggregation Prone Regions Underlie β-Aggregation in S100 Proteins

Intrinsically Disordered and Aggregation Prone Regions Underlie β-Aggregation in S100 Proteins

EFhd2 is a novel amyloid protein associated with pathological tau in Alzheimer's disease

S100A6 expression in cutaneous smooth muscle neoplasms

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